NEBIDO SOLUTION

Indication

Testosterone undecanoate is indicated as a testosterone replacement therapy in adult males that present conditions of deficiency or absence of endogenous testosterone. The approved conditions for the use of testosterone undecanoate are 1) primary hypogonadism, defined as a testicular failure due to cryptorchidism, bilateral torsion, orchitis, vanishing testis syndrome, orchiectomy, Klinefelter's syndrome, chemotherapy or toxic damage from alcohol or heavy metals: or 2) hypogonadotropic hypogonadism caused by idiopathic gonadotropin or luteinizing hormone-releasing hormone deficiency or pituitary-hypothalamic injuries from tumors, trauma or radiation.[FDA label]

Mechanism of Action

The effects of testosterone in humans and other vertebrates occur by way of two primary mechanisms: by activation of the androgen receptor (directly or as DHT), and by conversion to estradiol and activation of specific estrogen receptors. Free testosterone (T) is transported into the cytoplasm of target tissue cells, where it can bind to the androgen receptor, or can be reduced to 5-alpha-dihydrotestosterone (DHT) by the cytoplasmic enzyme 5-alpha-reductase. The T-receptor complex undergoes a structural change that allows it to move into the cell nucleus and bind directly to specific nucleotide sequences of the chromosomal DNA. The areas of binding are called hormone response elements (HREs), and influence transcriptional activity of certain genes, producing the androgen effects.[A949]

Pharmacokinetics

Absorption

The absorption of testosterone undecanoate relies on the presence of fat as it is only soluble in it. Thus, the bioavailability of this testosterone derivative is very low of just 7%.[A31633] This highly lipophilic profile delineates the absorption of testosterone to be done via the lymphatic system.[L1164] The reported Cmax in steady state for testosterone undecanoate is 32 nmol/L after 7 days of administration.[A31629]

Distribution

The distribution of testosterone undecanoate was limited to the liver, kidney and large and small intestine. Half of the administered dose remain near the injection site after 8 weeks of injection.[L1165] Following intravenous infusion of testosterone undecanoate, the reported volume of distribution was approximately 1 L/kg.[L1155]

Metabolism

To start its activity, testosterone undecanoate has to be processed by enzymes in the bloodstream. These enzymes will break the bond between the ester part of the molecule and the testosterone. Once separated, testosterone is metabolized to 17-keto steroids through two different pathways. The major active metabolites are estradiol and dihydrotestosterone (DHT). Testosterone is metabolized to DHT by steroid 5α-reductase in skin, liver and urogenital tract. In reproductive tissues, DHT is further metabolized to androstanediol.[L1152]

Elimination

Clearance

After intravenous administration of testosterone undecanoate, the observed clearance rate was 24.5 ml min/kg. This clearance rate indicated a fast metabolic elimination and explained the low bioavailability of this derivate of testosterone.[A31633]

Toxicity

Preclinical trials have shown induction of uterine tumors as well as an increase in the susceptibility to hepatoma. Testosterone undecanoate is known to increase the number of tumors and differentiation of chemically induced carcinomas. Administration of exogenous testosterone reversibly suppresses spermatogenesis.[L1165]

Active Ingredient/Synonyms

Testosterone undeconate | Testosterone undecylate | Testosterone undecanoate |